Pathology of Chronic Kidney Disease

Question 1

Which diseases predispose individuals to CKD?

Answer 1

• Hypertension
• Diabetes
• Obesity
• Childhood kidney disease
• Heart disease
• Family history of CKD

Question 2

What about the kidneys makes them vulnerable to disease?

Answer 2

• Renal blood flow = 400mL per 100g of tissue.
  
  • This is much greater than other well-perfused vascular beds (heart, liver and brain).
  • So, renal tissue might be exposed to a significant quantity of any harmful circulating substances.
• Glomerular filtration is dependent on high intra- and trans- glomerular pressure, rendering glomerular capillaries vulnerable to haemodynamic injury.
• The organisation of the nephron’s microvasculature facilitates the spreading of glomerular injury.
• Any decrease in preglomerular or glomerular perfusion leads to decrease in peritubular blood flow, which, depending on the degree of hypoxia, entails tubulointerstitial injury and tissue remodeling.

Question 3

What are the main causes of renal injury?

Answer 3

• Immunologic reactions
• Tissue hypoxia and ischaemia
• Exogenic agents like drugs
• Endogenous substances like glucose
• Genetic defects

Question 4

How does hypertension cause CKD?

Answer 4

• Hypertension causes thickening of the blood vessels which causes narrowing of the lumen.
• Due to narrowing of the lumen, there is less blood flow to the kidneys (nephrons).
• The afferent arteriole is a vessel which brings blood toward the Bowman’s capsule. But, with less blood flowing through due to hypertension there is a decrease in filtration, thus a decrease in GFR.
• When there is a decrease in blood flow to the nephron, there are cells in this area which detect this decrease and start to produce renin.
• This subsequently leads to the activation of the RAAS.
• The RAAS leads to increased HR and further hypertension. This is unfortunate because less blood is flowing to the kidneys and the kidney thinks that by increasing BP it will receive more blood; this might work for some time but eventually the vessel thickening will continue, and the lumen will narrow further.
• It is a viscous cycle!!
• This will eventually lead to glomerulosclerosis = thickening and hardening of the vessels in the bowman’s capsule within the glomerulus.
• Glomerulosclerosis inevitably leads to ischaemic injury and loss of the nephron.

Question 5

How does diabetes cause CKD?

Answer 5

• Diabetic neuropathy.
• As a result of diabetic neuropathy:
  
  • Mesangial expansion and mesangial cell proliferation.
  • Podocytopathy
    
    • Hypertrophy
    • Eventually atrophy
  • Glomerular basement membrane thickening.
  • Sclerosis.

Question 6

Describe the progression of CKD.

Answer 6

• When there is loss of nephrons in an area, the blood flow will shift to nephrons which are still functional.
• This leads to glomerular hyperfltration. During the early stages, this is tolerated and there is a big increase in GFR in the functional nephron.
• After some time, this hyperfiltration results in glomerulosclerosis because there is such high pressure.
• Eventually, this glomerulosclerosis will lead to loss of the functional nephron and the cycle continues.
• In the late stage, so much of the kidney function is lost that GFR decreases, urine output decreases and you retain waste, resulting in uraemia.
• This all leads to the clinical manifestations of CKD.

Question 7

Describe the cascade of events following renal damage.

Answer 7

• Regardless of the method of injury, once renal damage has occurred, a cascade of events ensues…
• Increased intraglomerular pressure with glomerular hypertrophy as the kidney attempts to adapt to nephron loss to maintain GFR.
• Increased glomerular permeability to macromolecules which may result in toxicity to the mesangial matrix causing mesangial cell expansion, inflammation, fibrosis and glomerular scarring.
• Renal injury = increased angiotensin II production, causing an up-regulation of TGF-β, contributing to colagen synthesis and renal scarring within the glomerulus.